Invasive infections (such as meningitis) and middle ear infections due to Haemophilus influenzas or Streptococcus pneumoniae (pneumococci) are a threat to infant health, and pneumococci are a hazard in the elderly. Relatively few capsular types account for the majority of such infections, which are preventable by antibody (Ab) to the respective capsular polysaccharides (CP). In infancy the challenge is the slow maturation of Ab responses to pure CP vaccines. Responsiveness can be accelerated by coupling CP antigens to a protein carrier ("conjugate vaccines"). Several biologics firms have devised candidate vaccines for H. influenzas type b (Hib, but the structural basis for immunogenicity (and failures thereof) is unclear. Our goal has been the definition of structural and other variables that determine immunogenicity of conjugate vaccines in the very young infant. Much progress has been made with the Hib CP although some variables remain to be clarified. The licensed multivalent pneumococcal CP vaccine appears ineffective for the institutionalized elderly and those with underlying disease. Part of the problem may be a decline in Ab responsiveness to particular CP serotypes. Specific goals in the continuation of this project are: 1) To further define structural factors governing immunogenicity of Hib oligosaccharides coupled to the protein CRM-197, 2) To analyze the role of T lymphocyte epitopes of the CRM-197 component upon its carrier activity, by testing the reactivity with a panel of CRM-197-reactive murine T cell clones and monoclonal Abs; 3) To pursue structure- immunogenicity relationships of conjugates of pneumococcal serotypes 6,14,18,19, and 23, which cause the bulk of infant disease and which, as CP, are poorly immunogenic in infancy, 4) To examine the immunogenicity of pneumococcal conjugates in elderly humans, especially serotypes (e.g., types 3 and 6) prevalent in old age and which, as cp, are poorly immunogenic. If the conjugates are immunogenic, we would examine whether (as in infants) "priming" with the conjugate increases the capacity for a response to the CP alone. If so, an oligovalent conjugate of problematic serotypes might prime the elderly for a broadly consistent response to the extant 23-valent CP vaccine.